There remains an urgent need for a SARS-CoV-2 vaccine as a primary countermeasure to mitigate and eventually contain the spread of COVID-19. The virus’s S glycoprotein makes an attractive vaccine target because it plays a key role in mediating virus entry and is known to be immunogenic (40). Neutralizing antibody responses against S have been identified in SARS-CoV-2−infected individuals (2), and several clinical trials for a SARS-CoV-2 vaccine will test S as an immunogen. While we focused on S, our comparative analyses of other proteins yielded similar conclusions: A randomly selected SARS-CoV-2 sequence could be used as a vaccine candidate, given the similarity of any sequence to the computationally derived optimum vaccine candidate (as defined by the MRCAs or consensus sequence based on all circulating sequences). Vaccines developed using any of these sequences should, theoretically, be effective against all circulating viruses. Vaccine developers could consider designing a vaccine insert with the D614G mutation in S, as this mutation has become dominant worldwide. While mutations that become fixed are often linked to the host immune pressure, this seems unlikely for the SARS-CoV-2 mutation D614G. Because this residue lies at the interface between two subunits, it would not be expected to be part of a critical epitope for vaccine-mediated protection (Fig. 4). As such, pseudoviruses with D614G were as susceptible to neutralization as those with the initial residue D614 (25). A mutation, S612L, that emerged in MERS-CoV after passaging the virus in the presence of two antibodies (in 5/15 clones after 20 passages) (41) warrants the evaluation of the analogous D614G mutation in SARS-CoV-2 for its ability to interfere with the recognition of a distal epitope. A more direct path to viral escape from antibody recognition would be mutations in the RBD, as described for influenza (42, 43). Importantly, we found no mutation in the RBD that was present in more than 1% of SARS-CoV-2 sequences (highest frequency was 0.2% N439K); such rare variants are unlikely to interfere with vaccine efficacy.